Methods and systems for calculating analyte levels

ABSTRACT

Disclosed are systems and methods for detecting analyte levels. These systems and methods may include a sensor configured for at least partial placement in an analyte-containing medium. The sensor may include one or more transducers and one or more diffusion barriers. The diffusion barriers may be arranged to delay diffusion of analyte to one transducer relative to another transducer. This delay may be used for purposes such as calculating and/or compensating for lag between a measured analyte level and a physiological analyte level of interest.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application Ser. No. 62/545,121, filed on Aug. 14, 2017,which is incorporated herein by reference in its entirety.

BACKGROUND Field of Invention

The present invention relates to calculating levels in a first mediumusing measurements from a second medium. More specifically, aspects ofthe present invention relate to using estimating the rate of change ofthe level in the second medium using a measurement of the level in thesecond medium and one or more diffusion barrier-delayed measurements ofthe level in the second medium. Even more specifically, aspects of thepresent invention relate to calculating a blood analyte level using ameasurement of an interstitial fluid analyte level and one or moremeasurements of diffusion barrier-delayed measurements of theinterstitial fluid analyte level to instantaneously estimate the rate ofchange of the interstitial fluid analyte level.

Discussion of the Background

Analyte monitoring systems may be used to monitor analyte levels, suchas analyte concentrations. One type of analyte monitoring system is acontinuous glucose monitoring (CGM) system. A CGM system measuresglucose levels throughout the day and can be very useful in themanagement of diabetes. Some analyte monitoring systems use measurementsindicative of analyte levels in interstitial fluid (“ISF”) to calculateISF analyte levels and then convert the ISF analyte levels to bloodanalyte levels. The analyte monitoring systems may display the bloodanalyte levels to a user. However, because ISF analyte levels lag behindblood analyte levels, accurate conversion of ISF analyte levels to bloodanalyte levels is difficult.

SUMMARY

Aspects of the present invention relate to improving the accuracy ofblood analyte levels displayed to a user.

One aspect of the invention may provide a sensor configured for at leastpartial placement in an analyte-containing medium. In some embodiments,the sensor may include a first transducer that exhibits one or moredetectable properties based on an amount or concentration of an analytein proximity to the first transducer. In some embodiments, the sensormay include a first diffusion barrier arranged such that, when thesensor is placed in the medium, analyte contained in the medium diffusesthrough the first diffusion barrier before reaching the firsttransducer, wherein the first diffusion barrier is configured such thatanalyte contained in the medium diffuses through the first diffusionbarrier at a first diffusion rate r₁. In some embodiments, the sensormay include a second transducer that exhibits one or more detectableproperties based on an amount or concentration of an analyte inproximity to the second transducer. In some embodiments, when the sensoris placed in the medium, diffusion of analyte contained in the medium tothe first transducer may delayed relative to diffusion of analytecontained in the medium to the second transducer.

In any of the above embodiments, the sensor may include a seconddiffusion barrier arranged such that, when the sensor is placed in themedium, analyte contained in the medium may diffuse through the seconddiffusion barrier before reaching the second transducer. In someembodiments, the second diffusion barrier is configured such thatanalyte contained in the medium diffuses through the second diffusionbarrier at a second diffusion rate r₂, wherein r₂ is greater than r₁.

In any of the above embodiments, the first diffusion barrier maycomprise an outer surface configured to be disposed adjacent theanalyte-containing medium, an inner surface disposed opposite the outersurface and adjacent the first transducer, and a first thickness definedbetween the outer surface and the inner surface of the first diffusionbarrier. In some embodiments, the second diffusion barrier may comprisean outer surface configured to be disposed adjacent theanalyte-containing medium, an inner surface disposed opposite the outersurface and adjacent the second transducer, and a second thicknessdefined between the outer surface and the inner surface of the seconddiffusion barrier. In some embodiments, the second thickness may begreater than the first thickness such that when the sensor is placed inthe medium, analyte diffusing from the medium will exhibit a greater lagtime diffusing through the second diffusion barrier than through thefirst diffusion barrier.

In any of the above embodiments, the first diffusion barrier may bedisposed over the first transducer, and the first diffusion barrier maybe configured such that, when the sensor is placed in the medium, thefirst diffusion barrier at least partially inhibits diffusion of analyteto the second transducer.

In any of the above embodiments, the second diffusion barrier may bedisposed over the second transducer, and the second diffusion barriermay be configured such that, when the sensor is placed in the medium,the second diffusion barrier at least partially inhibits diffusion ofanalyte to the second transducer, and the first diffusion barrierinhibits diffusion of analyte to a greater degree than the seconddiffusion barrier.

In any of the above embodiments, the sensor may include a thirdtransducer that exhibits one or more detectable properties based on anamount or concentration of an analyte in proximity to the thirdtransducer. In some embodiments, the sensor may further include a thirddiffusion barrier arranged such that, when the sensor is placed in themedium, analyte contained in the medium may diffuse through the thirddiffusion barrier before reaching the third transducer. In someembodiments, the third diffusion barrier may be configured such thatanalyte contained in the medium diffuses through the third diffusionbarrier at a third diffusion rate r₃, wherein r₁ is greater than r₃.

In any of the above embodiments, the second transducer may be arrangedsuch that, when the sensor is placed in the medium, analyte contained inthe medium need not diffuse through a diffusion barrier before reachingthe second transducer.

In a second aspect, which may be combinable with features of any of theabove embodiments, an analyte detection system may include a sensorconfigured for at least partial placement in an interstitial fluid. Insome embodiments, the sensor may include a first transducer thatexhibits one or more detectable properties based on an amount orconcentration of an analyte in proximity to the first transducer. Insome embodiments, the sensor may include a first diffusion barrierarranged such that when the sensor is placed in the interstitial fluid,analyte contained in the interstitial fluid may diffuse through thefirst diffusion barrier before reaching the first transducer. In someembodiments, the first transfusion barrier may be configured such thatanalyte contained in the interstitial fluid diffuses through the firstdiffusion barrier at a first diffusion rate r₁. In some embodiments, thesensor may include a second transducer that exhibits one or moredetectable properties based on an amount or concentration of an analytein proximity to the second transducer element. In embodiments, thesystem may include a transceiver configured to receive first sensor datacollected from the first transducer. In some embodiments, thetransceiver may be configured to receive second sensor data collectedfrom the second transducer. In some embodiments, the transceiver may beconfigured to calculate an interstitial fluid analyte level rate ofchange based on at least the first sensor data, the second sensor data,and r₁.

In any of the above embodiments of the second aspect, the system maycomprising a second diffusion barrier arranged such that when the sensoris placed in the interstitial fluid, analyte contained in theinterstitial fluid may diffuse through the second diffusion barrierbefore reaching the first transducer. In some embodiments, the secondtransfusion barrier may be further configured such that analytecontained in the interstitial fluid diffuses through the seconddiffusion barrier at a second diffusion rate r₂, r₂ being greater thanr₁. In embodiments, calculating the interstitial fluid analyte levelrate of change may be further based on r₂.

In a third aspect, which may be combinable with features of any of theabove embodiments, a method for detecting the rate of change of ananalyte concentration in a medium may be provided. In some embodiments,the method may include receiving from a sensor at least first sensordata corresponding to a first measurement of a detectable propertyexhibited by a first transducer and second sensor data corresponding toa second measurement of a detectable property exhibited by a secondtransducer. In some embodiments, the first sensor data may be indicativeof an amount or concentration of an analyte in proximity to the firsttransducer after passing through a first diffusion barrier. In someembodiments, the method may include calculating an analyte level rate ofchange based on at least the first sensor data, the second sensor data,and a first diffusion rate r₁ of the analyte through the first diffusionbarrier.

In any of the above embodiments of the third aspect, a detectableproperty exhibited by the second transducer may be indicative of anamount or concentration of the analyte in proximity to the secondtransducer after passing through a second diffusion barrier. In someembodiments, calculating the analyte level rate of change may be furtherbased on a second diffusion rate r₂ of the analyte through the seconddiffusion barrier, r₂ being greater than r₁.

In any of the above embodiments of the third aspect, the method mayinclude calculating an interstitial fluid analyte level based on atleast one of the first sensor data and the second sensor data. In someembodiments, the method may include calculating a blood analyte levelbased on the interstitial fluid analyte level and the analyte level rateof change.

In any of the above embodiments of the third aspect, the method mayinclude detecting that a transceiver is positioned within a proximity ofthe sensor. In some embodiments, the method may include transmitting, inresponse to detecting that the transceiver is proximate the sensor, fromthe transceiver to the sensor power sufficient to perform the firstmeasurement and the second measurement, the transmitted power being usedto perform the first measurement and the second measurement. In someembodiments, the method may include removing the transceiver from theproximity of the sensor. In some embodiments, this removing step mayoccur after receiving from the sensor the first sensor data and thesecond sensor data, and before additional measurements are performed.

Further variations encompassed within the systems and methods aredescribed in the detailed description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate various, non-limiting embodiments ofthe present invention. In the drawings, like reference numbers indicateidentical or functionally similar elements.

FIG. 1 is a schematic view of an analyte monitoring system embodiment,which includes an implantable sensor and a transceiver.

FIG. 2 illustrates a longitudinal view of a sensor embodying aspects ofthe present invention.

FIG. 3 illustrates a longitudinal view of a sensor embodying aspects ofthe present invention.

FIG. 4 illustrates a cross-sectional view of a sensor embodying aspectsof the present invention.

FIGS. 5 and 6 illustrate perspective views of a sensor embodying aspectsof the present invention.

FIG. 7 illustrates perspective views of a sensor embodying aspects ofthe present invention.

FIG. 8 illustrates a side view of a sensor embodying aspects of thepresent invention.

FIG. 9 illustrates a diagram of a sensor implanted subcutaneouslyaccording to embodiments of the present invention.

FIG. 10 illustrates a schematic diagram of a sensor having multiplediffusion barriers according to aspects of the present invention.

FIG. 11 is a flow chart illustrating a process for calculating analytelevels embodying aspects of the present invention.

FIG. 12 is a schematic diagram of a transceiver according to aspects ofthe present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1 is a schematic view of an analyte monitoring system embodyingaspects of the present invention. In one non-limiting embodiment, thesystem includes a sensor 100 and an external transceiver 101. In theembodiment shown in FIG. 1, the sensor 100 is implanted in a livinganimal (e.g., a living human). The sensor 100 may be implanted, forexample, in a living animal's arm, wrist, leg, abdomen, or other regionof the living animal suitable for sensor implantation. For example, asshown in FIG. 1, in one non-limiting embodiment, the sensor 100 may beimplanted between the skin and subcutaneous tissues. In someembodiments, the sensor 100 may be an optical sensor. In someembodiments, the sensor 100 may be a chemical or biochemical sensor.

In some embodiments, as illustrated in FIG. 1 and FIG. 12, thetransceiver 101 may be an electronic device that communicates with thesensor 100 to power the sensor 100 and/or obtain analyte (e.g., glucose)readings from the sensor 100. In some non-limiting embodiments, thetransceiver 101 may be a handheld reader, a wristwatch, waistband,armband, keychain attachment, or it may be incorporated within or acomponent of a user device 10 (e.g., a smartphone, personal dataassistant, handheld device, or laptop computer). In other non-limitingembodiments, the transceiver 101 may be held on a user's body byadhesive (e.g., as part of a biocompatible patch). In some embodiments,positioning (i.e., hovering or swiping/waiving/passing) the transceiver101 within range over the sensor implant site (i.e., within proximity ofthe sensor 100) may cause the transceiver 101 to automatically convey ameasurement command to the sensor 100 and receive a reading from thesensor 100.

In some embodiments, as shown in FIG. 12, the transceiver 101 mayinclude one or more of an antenna 1203 and a processor 1205. Theprocessor 1205 may perform one or more of steps 1102, 1104, 1110, and1112 as illustrated in FIG. 11 and discussed below. In some embodiments,the transceiver may include a user interface 1207. In one non-limitingembodiment, the user interface 1207 may include one or more of a liquidcrystal display (LCD) and vibration motor, but, in other embodiments,different types of user interfaces may be used, or the transceiver 101may not include a user interface.

In some embodiments, the antenna 1203 may include an inductive element,such as, for example, a coil. In some embodiments, the antenna 1203 maygenerate an electromagnetic wave or electrodynamic field (e.g., by usinga coil) to induce a current in an inductive element of the sensor 100,which may power the sensor 100 via an inductive element (e.g., inductiveelement 114 of FIGS. 2-3) disposed in the sensor 100 and configured toreceive and/or transmit electromagnetic waves or electrodynamic fieldsfrom and/or to the transceiver antenna 1203. In some embodiments, theantenna 1203 may additionally or alternatively convey data (e.g.,commands) to the sensor 100. For example, in a non-limiting embodiment,the antenna 1203 may convey data by modulating the electromagnetic waveused to power the sensor 100 (e.g., by modulating the current flowingthrough a coil of the antenna 1203). The modulation in theelectromagnetic wave generated by the transceiver 101 may bedetected/extracted by the sensor 100. Moreover, the antenna 1203 mayreceive data (e.g., measurement information) from the sensor 100. Forexample, in a non-limiting embodiment, the antenna 1203 may receive databy detecting modulations in the electromagnetic wave generated by thesensor 100, e.g., by detecting modulations in the current flowingthrough the coil of the antenna 1203.

The inductive element of the transceiver 101 and the inductive element(e.g., inductive element 114 illustrated in FIGS. 2-3) of the sensor 100may be in any configuration that permits adequate field strength to beachieved when the two inductive elements are brought within adequatephysical proximity.

In some embodiments, the processor 1205 may calculate one or moreanalyte concentrations based on the analyte readings received from thesensor 100. In some embodiments, the processor 1205 may also generateone or more alerts and/or alarms based on the calculated analyteconcentrations (e.g., if the calculated analyte concentration exceeds orfalls below one or more thresholds). The calculated analyteconcentrations, alerts, and/or alarms may be communicated (e.g.,displayed) via the user interface 1207.

In some embodiments, the transceiver 101 may communicate (e.g., using awireless communication standard, such as, for example and withoutlimitation, Bluetooth) with a user device (e.g., a smartphone, personaldata assistant, handheld device, or laptop computer). In otherembodiments, the transceiver 101 may be incorporated within or acomponent of a user device. In some embodiments, the user device mayreceive calculated analyte concentrations, alerts, and/or alarms fromthe transceiver 101 and display them. Display by the user device may bein addition to, or in the alternative to, display by the user interface1207 of the transceiver 101. For example, in some embodiments, asillustrated in FIG. 1, the transceiver 101 may include a user interface1207, but this is not required. In some alternative embodiments, thetransceiver 101 may not have a user interface 1207, and calculatedanalyte concentrations, alerts, and/or alarms may instead be displayedby a user device. In other embodiments, the transceiver 101 may beincorporated within or a component of a user device, and the transceiver101 and user device may share a user interface and/or display.

In some non-limiting embodiments, the transceiver 101 and sensor 100 mayhave some or all of the structure described in U.S. Pat. Nos. 9,414,775and 9,427,182, which are incorporated by reference in their entireties.

FIGS. 2-3 illustrate aspects of non-limiting examples of a sensor 100that may be used in the analyte monitoring system illustrated in FIG. 1.In some embodiments, the sensor 100 may be an optical sensor. In onenon-limiting embodiment, sensor 100 includes a sensor housing 102 (i.e.,body, shell, or capsule). In exemplary embodiments, sensor housing 102may be formed from a suitable, optically transmissive polymericmaterial, such as, for example, acrylic polymers (e.g.,polymethylmethacrylate (PMMA)).

In some embodiments, the sensor 100 may include one or more of a firsttransducer 107 and a second transducer 106. In some embodiments, thefirst transducer 107 may include one or more first indicator molecules105. In some non-limiting embodiments, the second transducer 106 mayinclude one or more second indicator molecules 104. In some embodiments,the first and second indicator molecules 105, 104 may be fluorescentindicator molecules or absorption indicator molecules. In somenon-limiting embodiments, the first and second indicator molecules 105,104 may be as described in U.S. Pat. No. 6,344,360 or 9,414,775, whichare incorporated herein by reference in their entireties. In somenon-limiting embodiments, one or more of the transducers 106, 107 mayinclude a polymer graft (e.g., matrix layer or hydrogel) coated orembedded on or in at least a portion of the exterior surface of thesensor housing 102. In some non-limiting embodiments, first and secondindicator molecules 105, 104 may be distributed throughout the polymergraft. In some embodiments, the first and second transducers 107, 106may be embedded within the sensor housing 102. In some embodiments, thefirst and second transducers 107, 106 may cover the entire surface ofsensor housing 102 or only one or more portions of the surface ofhousing 102. In some non-limiting embodiments, the first indicatormolecules 105 may be distributed throughout the entire first transducer107 or only throughout one or more portions of the first transducer 107.In some non-limiting embodiments, the second indicator molecules 104 maybe distributed throughout the entire second transducer 106 or onlythroughout one or more portions of the second transducer 106.

In some embodiments, as shown in FIGS. 2-4, the sensor 100 may includeone or more light sources 108, which may be, for example, a lightemitting diode (LED) or other light source that emits light over a rangeof wavelengths that interact with the first and second indicatormolecules 105, 104. In some embodiments, the second indicator molecules104 may be chemically identical to first indicator molecules 105, and/ormay interact with and/or emit the same or similar wavelengths of light.In other embodiments, the second indicator molecules 104 may differ fromthe first indicator molecules 105, and/or may interact with and/or emitdifferent wavelengths of light.

In some embodiments, the sensor 100 may include one or morephotodetectors 224, 226 (e.g., photodiodes, phototransistors,photoresistors, or other photosensitive elements). In some embodiments,the one or more photodetectors of the sensor 100 may include one or moresignal photodetectors 226 that may be sensitive to emission light (e.g.,fluorescent light) emitted by the indicator molecules 104, 105 such thata signal may be generated by the photodetectors 224 in response theretothat is indicative of the level of the indicator molecules 104, 105 and,thus, the concentration of analyte of interest (e.g., glucose). In someembodiments, as shown in FIGS. 2-4, the one or more signalphotodetectors 226 may include at least one first signal photodetector226 a configured to receive first emission light 331 a emitted by thefirst indicator molecules 105 of the first transducer 107 and to outputa signal indicative of an amount thereof. In some embodiments, as shownin FIGS. 2-4, the one or more signal photodetectors 226 may include atleast one second signal photodetector 226 b configured to receive secondemission light 331 b light emitted by the second indicator molecules 104of the second transducer 106 and to output a signal indicative of anamount thereof.

In some embodiments, the one or more photodetectors of the sensor 100may include one or more reference photodetectors 224 that may besensitive to excitation light 329 (e.g., ultraviolet light) emitted bythe one or more light sources 108 such that a signal may be generated bythe photodetectors 226 in response thereto that is indicative of anamount of excitation light 329 reflected by the first and secondtransducers 107, 106. In some embodiments, as shown in FIGS. 2-4, theone or more reference photodetectors 226 may include at least one firstreference photodetector 224 a configured to receive excitation light 329reflected by the first transducer 107 and to output a signal indicativeof an amount thereof. In some embodiments, as shown in FIGS. 2-4, theone or more reference photodetectors 224 may include at least one secondreference photodetector 224 b configured to receive excitation light 329reflected by the second transducer 106 and to output a signal indicativeof an amount thereof.

As illustrated in FIGS. 2-4, some embodiments of sensor 100 include oneor more optical filters 112 a, 112 b, 113 a, 113 b, such as high pass orband pass filters, and the sensor 100 may be configured such that lightpasses through an optical filter 112 a, 112 b, 113 a, or 113 b beforereaching a photosensitive side of the one or more photodetectors 224 a,224 b, 226 a, 226 b. In some non-limiting embodiments, the one or moreoptical filters 112 a, 112 b, 113 a, 113 b may cover a photosensitiveside of the one or more photodetectors 224 a, 224 b, 226 a, 226 b,respectively.

In some embodiments, sensor 100 may be wholly self-contained. In otherwords, the sensor may be constructed in such a way that no electricalleads extend into or out of the sensor housing 102 to supply power tothe sensor (e.g., for driving a light source 108) or to convey signalsfrom the sensor 100. In some non-limiting embodiments, the sensor 100may be powered by an external power source (e.g., external transceiver101). For example, the external power source may generate a magneticfield to induce a current in an inductive element 114 (e.g., a coil orother inductive element). In some embodiments, the sensor 100 may usethe inductive element 114 to communicate information to an externalsensor reader (e.g., transceiver 101). In some embodiments, the externalpower source and data reader may be the same device (e.g., transceiver101). In some embodiments, an antenna 1203 of transceiver 101 may bearranged as a coil that wraps around the sensor 100. In otherembodiments, the sensor may have a different configuration, such as, forexample, those described in U.S. patent application Ser. No. 13/650,016,which is incorporated herein by reference in its entirety, withparticular reference to FIGS. 2A-2C, or those described in U.S. Pat. No.9,414,775, which is incorporated herein by reference in its entirety.

In some embodiments, the sensor 100 may include a substrate 116. In somenon-limiting embodiments, the substrate 116 may be a semiconductorsubstrate and circuitry may be fabricated in the semiconductor substrate116 (see FIG. 4). In some embodiments, the circuitry may include analogand/or digital circuitry. In some embodiments, the circuitry mayincorporate some or all of the structure described in U.S. patentapplication Ser. No. 13/650,016, which is incorporated herein byreference in its entirety, with particular reference to FIG. 11D.Although in some embodiments the circuitry may be fabricated in thesemiconductor substrate 116, in alternative embodiments, a portion orall of the circuitry may be mounted or otherwise attached to thesemiconductor substrate 116. In other words, in alternative embodiments,a portion or all of the circuitry may include discrete circuit elements,an integrated circuit (e.g., an application specific integrated circuit(ASIC)) and/or other electronic components discrete and may be securedto the semiconductor substrate 116, which may provide communicationpaths between the various secured components. In some alternativeembodiments, the substrate 116 may be a printed circuit board.

In some embodiments, the one or more photodetectors 224, 226 may bemounted on the semiconductor substrate 116, but, in some embodiments, asshown in FIG. 4, the one or more photodetectors 224, 226 may befabricated in the semiconductor substrate 116. In some embodiments, theone or more light sources 108 may be mounted on the semiconductorsubstrate 116. For example, in a non-limiting embodiment, the lightsource(s) 108 may be flip-chip mounted on the semiconductor substrate116. However, in some embodiments, the light source(s) 108 may befabricated in the semiconductor substrate 116.

According to one aspect of the invention, the sensor 100 may beconfigured to measure various biological analytes in the living body ofan animal (including a human). For example, sensor 100 may be used tomeasure glucose, oxygen toxins, pharmaceuticals or other drugs,hormones, and other metabolic analytes in, for example, the human body.The specific composition of the transducers 106, 107 and the indicatormolecules 104, 105 therein may vary depending on the particular analytethe sensor is to be used to detect and/or where the sensor is to be usedto detect the analyte (i.e., in interstitial fluid). The transducers106, 107 may facilitate exposure of the indicator molecules 104, 105 tothe analyte. The optical characteristics of the indicator molecules(e.g., the level of fluorescence of fluorescent indicator molecules) maybe a function of the concentration of the specific analyte to which theindicator molecules are exposed.

In some embodiments, one or more the light sources 108 may be positionedto emit excitation light 329 that travels within the sensor housing 102and reaches the first and second indicator molecules 105, 104 of thefirst and second transducers 107, 106, respectively. In someembodiments, the photodetectors 224 a, 226 a, which may be locatedbeneath filters 112 a, 113 a, may be positioned to receive light fromthe first indicator molecules 105 of the first transducer 107. In someembodiments, the photodetectors 224 b, 226 b, which may be locatedbeneath filters 112 b, 113 b, may be positioned to receive light fromthe second indicator molecules 104 of the second transducer 106.

In operation, as shown in FIGS. 2-4, the light source(s) 108 may emitexcitation light 329 that travels within the sensor housing 102 andreaches the first and second indicator molecules 104, 105 of the firstand second transducers 106, 107. In a non-limiting embodiment, theexcitation light 329 may cause the indicator molecules 104, 105distributed in transducers 106, 107 to emit light (e.g., to fluoresce).In some embodiments, the transducers 106, 107 may be permeable to theanalyte (e.g., glucose) in the medium (e.g., blood or interstitialfluid) into which the sensor 100 is implanted. Accordingly, in someembodiments, the first and second indicator molecules 105, 104 in thefirst and second transducers 107, 106, respectively, may interact withthe analyte in the medium and, when irradiated by the excitation light329, may emit first and second emission light 331 a, 331 b,respectively, which may be indicative of the presence and/orconcentration of the analyte in the medium. In some embodiments, the oneor more of the first and second emission light 331 a and 331 b may be,for example and without limitation, fluorescent light.

In some embodiments, the photodetectors 224, 226 may receive light. Insome embodiments, the one or more photodetectors 224 may be covered byfilters 112, and the one or more photodetectors 226 may be covered byfilters 113. In some embodiments, the filters 112, 113 may allow only acertain subset of wavelengths of light to pass through. In someembodiments, the filters 112, 113 may be thin film (e.g., dichroic)filters deposited on glass, and the filters 112, 113 may pass only anarrow band of wavelengths and otherwise reflect (or absorb) theremaining light. In some embodiments, the filters 112, 113 may beidentical (e.g., each filter 112, 113 may allow signal light to pass) ordifferent (e.g., filters 112 may allow signal light to pass, and filters113 may allow reference light to pass). In some embodiments where thefirst and second indicator molecules 105, 104 emit light at differentwavelengths, the signal light filter 112 a may be configured to passlight 331 a emitted by the first indicator molecules 105 to the firstsignal photodetector 226 a but to reflect (or absorb) the excitationlight 329 and the light 331 b emitted by the second indicator molecules104. Similarly, the signal light filter 112 b may be configured to passlight 331 b emitted by the second indicator molecules 104 to the secondsignal photodetector 226 b but to reflect (or absorb) the excitationlight 329 and the light 331 a emitted by the first indicator molecules105. In this manner, the first and second signal photodetectors 226 aand 226 b disposed under the signal light filters 112 a and 112 b,respectively, may be selected to receive only a respective one of light331 a and 331 b emitted by the first and second indicator molecules 104,105 of the first and second transducer 107, 106, respectively.

In some embodiments, the filters 113 may pass light at the samewavelength as the wavelength of the excitation light 329 emitted fromthe light source 108 (e.g., 378 nm). In some embodiments, firstindicator molecules 105 and second indicator molecules 104 may beexcited by light emitted at different wavelengths. In such embodiments,multiple (e.g., two) light sources 108 may be provided, wherein onelight source 108 emits light at a wavelength capable of excitingindicator molecules 105, and a second light source 108 emits light at awavelength capable of exciting indicator molecules 104.

Photodetectors 226 a, 226 b may be signal photodetectors that detect theamount of fluoresced light 331 that is emitted from the first and secondindicator molecules 104, 105 in the first and second transducers 106,107. In some non-limiting embodiments, the signal filters 112 a, 112b—which may in some embodiments cover photodetectors 224 a, 224 b—maypass light in the range of about 400 nm to 500 nm. Higher analyte levelsmay correspond to a greater amount of fluorescence of the molecules 105,106 in the transducers 106, 107, and therefore, a greater amount ofphotons striking the signal photodetectors 226.

As illustrated in FIGS. 2-4, a diffusion barrier 120 may be disposed onor over a portion of the sensor body 102. In some embodiments, thediffusion barrier 120 may be formed as a membrane, graft, mesh,sputtered layer, or any other structural arrangement configured topermit at least partial diffusion of analyte therethrough. When thesensor 100 is implanted, for example in a medium such as interstitialfluid, analyte may diffuse through the diffusion barrier 120 beforereaching the transducer 107. The diffusion barrier 120 may have anassociated diffusion rate r, which may represent the rate at whichanalyte may diffuse across the diffusion barrier 120. The diffusionbarrier 120 may further have an associated lag time τ, which mayrepresent the time for analyte to diffuse across the diffusion barrier120. The lag time τ and diffusion rate r may be inversely related (e.g.,τ may be equal to 1/r). Values for both lag time τ and diffusion rate rmay be determined or measured in advance through quality assurance ortesting practices.

In some embodiments, such as that illustrated in FIG. 2, only onetransducer 107 is covered by a diffusion barrier 120. In this manner,analyte in the medium will reach the transducer 107 at a delay (whichmay correspond to lag time τ) relative to when it reaches transducer106. Thus, signal received from the transducer 106 may be indicative ofcurrent analyte levels proximate the sensor 100, and signal receivedfrom the transducer 107 may be indicative of analyte levels proximatethe sensor 100 at a time period (which may correspond to lag time τ)prior to the time at which the measurement signal is received. Bycomparing the measurements from the transducers 106, 107, an analytelevel rate of change proximate the sensor 100 may be calculated. In someembodiment, this rate of change may be calculated based on measurementdata received from the first transducer 107, measurement data receivedfrom the second transducer 106, and the diffusion rate r and/or lag timeτ of the diffusion barrier 120.

In other exemplary embodiments, as illustrated in FIG. 3, the firsttransducer 107 may be covered by a first diffusion barrier 120, and thesecond transducer 106 may be covered by a second diffusion barrier 121.The first and second diffusion barriers 120 and 121 may have differentdiffusion characteristics. For example, the first diffusion barrier 120may have a first diffusion rate r₁ and a first lag time τ₁, and thesecond diffusion barrier 121 may have a second diffusion rate r₂ and asecond lag time τ₂, each different than the respective values for thediffusion barrier 120. Values for the diffusion rates and lag times maybe determined or measured in advance through quality assurance ortesting practices. Signal received from the first transducer 107 may beindicative of analyte levels proximate the sensor 100 at a time period(which may correspond to lag time τ₁) prior to the time at which themeasurement signal is received, and signal received from the secondtransducer 106 may be indicative of analyte levels proximate the sensor100 at a time period (which may correspond to lag time τ₂) prior to thetime at which the measurement signal is received. By comparing themeasurements from the first and second transducers 107, 106, an analytelevel rate of change proximate the sensor 100 may be calculated. In someembodiment, this rate of change may be calculated based on measurementdata received from the first transducer 107, measurement data receivedfrom the second transducer 106, the diffusion rate r₁ and/or lag time τ₁of the diffusion barrier 120, and the diffusion rate r₂ and/or lag timeτ₂ of the diffusion barrier 121.

A difference between the diffusion rates (and lag times) of thediffusion barriers 120, 121 may be effected by varying any of a varietyof characteristics of the respective diffusion barriers 120, 121. Forexample, as illustrated in FIG. 3, the diffusion barriers 120, 121 mayhave different thicknesses. In other embodiments, the diffusion barriers120, 121 may have different porosities or structural characteristics(e.g., channels) allowing passage of analyte. In still otherembodiments, the diffusion barriers 120, 121 may have different chemicalcompositions, such that one of the barriers may be more or lesshydrophobic or hydrophilic than the other. Other arrangements forcontrolling the diffusion rates of the diffusion membranes may be used.

Although one diffusion barrier 120 is shown in FIGS. 2 and 4 and twodiffusion barriers 120 and 121 are shown in FIG. 3, in some embodiments,the sensor 100 may include more than two diffusion barriers. Forexample, as shown in FIG. 10, the sensor 100 may include first, second,and third diffusion barriers 120, 121, and 122, each with differingdiffusion characteristics. In other embodiments, the sensor 100 may havemore than three diffusion barriers with differing diffusioncharacteristics.

Similarly, although two transducers 106 and 107 are shown in FIGS. 2-4,in some embodiments, the sensor 100 may include more than twotransducers. For example, as shown in FIG. 10, the sensor 100 mayinclude first, second, third, and fourth transducers 107, 106, 1008, and1009. In some embodiments, the sensor 100 may use the additionaltransducers with additional diffusion barriers to measure simultaneouslyanalyte levels at additional lag times. In some embodiments, thetransceiver 101 may use these additional measurements to obtain a moreaccurate estimate for the analyte level rate of change proximate thesensor body 102. In some non-limiting embodiments, the transceiver 101perform non-linear regression to calculate the analyte level rate ofchange using the differently delayed analyte levels.

As illustrated in FIGS. 3 and 4, the transducers 106, 107 may be axiallyarranged along the length of the sensor body 102, such that thetransducer 107 is disposed along a first axial portion of the sensorbody 102, and the transducer 106 is disposed along a second axialportion of the sensor body 102, the first axial portion being differentthan the first. The photodetectors 224, 226 and optical filters 112, 113may also be axially arranged, such that the photodetectors 224, 226 andoptical filters 112, 113 for measuring signal from the transducer 107may be disposed along the first axial portion of the sensor body 102,and the photodetectors 224, 226 and optical filters 112, 113 formeasuring signal from the transducer 106 may be disposed along thesecond axial portion of the sensor body 102.

FIG. 4 shows a cross-sectional view of another exemplary embodiment of asensor 100. In some embodiments, as illustrated in FIG. 4, thetransducers 106, 107 may be circumferentially arranged along theperimeter of the sensor body 102, such that the transducer 107 isdisposed along a first perimeter portion of the sensor body 102, and thetransducer 106 is disposed along a second perimeter portion of thesensor body, the first perimeter portion being different than the first.

The embodiment illustrated in FIG. 4 features many of the same elementsand function as discussed above with respect to FIGS. 2 and 3. Here,however, a divider member 130 may be disposed between the transducers106 and 107. The divider member 130 may be opaque to the wavelengths oflight emitted by the transducers 106 and 107 and/or the light source108, thereby isolating the measurement signals received from therespective transducers 106, 107. In embodiments in which an opaquedivider member 130 is provided, signal produced by the first and secondtransducers 107, 106 may be naturally isolated. The first and secondindicator molecules 105, 104 of the first and second transducers 107,106, respectively, may emit light at the same wavelength or at differentwavelengths.

FIGS. 5-8 illustrate exemplary arrangements for providing a diffusionbarrier over one or more of the first and second transducers 107, 106.FIG. 5 illustrates a sensor 100 without a diffusion barrier 120, andFIG. 6 shows the sensor 100 with the diffusion membrane 120. In somenon-limiting embodiments, the sensor 100 may have a sensor housing/shell102 and transducers 106, 107 embedded within and/or covering at least aportion of the housing 102. In some embodiments, the first transducer107 may include one or more first indicator molecules 105, and thesecond transducer 106 may include one or more second indicator molecules104, as discussed above.

In some embodiments, the diffusion barrier 120 may be a polymer membranethat is deposited over the surface of sensor body 102. The polymermembrane may then be partially or fully removed from a portion of thesensor body 102, such as directly over transducer 106 to thereby reducethe diffusion lag time associated with transducer 106. In otherembodiments, the lag time may be selectively controlled by machining orprocessing the membrane after deposition on the sensor body. In stillother embodiments, portions of the sensor body 102 may be wrapped in aremovable material prior to applying the polymer membrane, therebyselectively preventing or inhibiting the membrane from being depositedover the transducer 106 and/or other portions of the sensor body 102.

As illustrated in the exemplary embodiment of FIG. 7, a mesh 320 may beprovided over a portion 303 of the sensor body 302. One or more of thetransducers may be disposed within the sensor body portion 303. The mesh320 may itself act as a diffusion barrier. For example, mesh fibers(e.g., metallic or polymeric fibers) may be woven at selected densitiesin order to selectively control the diffusion characteristics atdifferent positions along the mesh 320. In other embodiments, a graftmaterial (e.g., a polymeric graft) may be affixed to the mesh 320, whichmay then be affixed at a selected portion of the sensor body 302 (seealso FIG. 6, depicting a polymeric graft affixed to a selected portionof a sensor body).

FIG. 8 illustrates an exemplary embodiment in which a material isselectively sputtered onto a portion 403 of a sensor body 402, therebyforming a diffusion barrier 420. As shown in FIG. 8, the diffusionbarrier 420 may cover transducer 407 but not transducer 406. In otherembodiments, the diffusion barrier 420 may cover both transducer 406 and407, but may be deposited to form a thicker or denser coating overtransducer 407 relative to transducer 406.

FIG. 9 depicts a diagram in which a sensor 100 is implanted within theinterstitial fluid under a subject's skin and proximate to a capillary.In some embodiments, it may be desired to precisely estimate aconcentration of analyte contained within the subject's blood. Forexample, the analyte monitoring system may be used to estimate a bloodglucose level within a capillary as depicted in FIG. 9. Analytemolecules (e.g., glucose) may diffuse from the capillary through theinterstitial fluid toward the sensor 100. After reaching the sensor 100,the analyte molecules may diffuse through any diffusion barriers andinto the transducers to interact with indicator molecules disposedtherein. The sensor 100 is able to detect analyte concentration when theanalyte molecules reach and interact with the indicator moleculescontained in the transducers.

In human subjects with diabetes, meanwhile, blood analyte concentrationmay change significantly over time, which in turn causes theinterstitial fluid analyte concentration (C_(ISF)) to change over time.Due to the lag time required for analyte to diffuse from the capillarythrough the interstitial fluid to the sensor transducers, measurementaccuracy can be improved by calculating the interstitial fluid rate ofchange (R_(ISF)), and using the measured C_(ISF) in combination with thecalculated R_(ISF) to estimate the current blood analyte level. By usingat least two transducers associated with different lag times asdescribed above, it is possible to determine the R_(ISF) with a singlemeasurement (e.g., by performing a swipe measurement).

FIG. 11 is a flow chart illustrating an exemplary process 1100 formeasuring an analyte concentration. In some embodiments, the process1100 may include a step 1102 in which a transceiver 101 may detect thatit is positioned within a proximity of a sensor 100. For example, thesensor may be subcutaneously implanted within an analyte-containingmedium (e.g., interstitial fluid), and the transceiver 101 may beswiped, waved, or held within the sensor proximity. The proximitydetection may be performed according to the systems and processesdiscussed in U.S. patent application Ser. No. 13/650,016, which isincorporated by reference in its entirety.

In some embodiments, the process 1100 may include a step 1104 in which,in response to detecting that the transceiver is proximate the sensor,the transceiver 101 may transmit to the sensor power sufficient toperform at least a first measurement using a first transducer 107 of thesensor 100 and a second measurement using a second transducer 106 of thesensor 100. Power may be transmitted via inductive elements as describedabove with respect to FIGS. 1-3. The transceiver 101 may also transmitone or more commands to the sensor 100, the one or more commandsinstructing the sensor 100 to perform one or more measurements, such asthe first and second measurements described above.

In some embodiments, the method 1100 may include a step 1106 in whichthe sensor 100 may perform a first measurement of a detectable propertyexhibited by a first transducer 107 and a second measurement of adetectable property exhibited by a second transducer 106. The first andsecond transducers 107, 106 may exhibit one or more detectableproperties based on an amount or concentration of an analyte inproximity to the respective first and second transducers 107, 106. Insome embodiments, the first measurement may be indicative of an amountor concentration of an analyte in proximity to the first transducer 107after passing through a first diffusion barrier 120. In someembodiments, the second measurement may be indicative of an amount orconcentration of an analyte in proximity to the second transducer 106after passing through a second diffusion barrier 121 (if present). Insome embodiments, one or more of the first measurement and secondmeasurement may be performed using the power transmitted in step 1204.

In some embodiments (e.g., embodiments in which the sensor 100 has morethan two transducers associated with different time lags (see FIG. 10)),the sensor 100 may perform one or more additional measurements of adetectable property of the one or more additional transducers. In someembodiments, the additional transducers (e.g., third and fourthtransducers 1008 and 1009 of FIG. 10) may exhibit one or more detectableproperties based on an amount or concentration of an analyte inproximity to the one or more additional transducers. In someembodiments, a third measurement may be indicative of an amount orconcentration of an analyte in proximity to the third transducer 1008after passing through a second diffusion barrier 121. In someembodiments, the fourth measurement may be indicative of an amount orconcentration of an analyte in proximity to a fourth transducer 1009after passing through a third diffusion barrier 122. In someembodiments, the third and/or fourth measurements may be performed usingthe power transmitted in step 1104.

In some embodiments, the method 1100 may include a step 1108 in whichthe sensor 100 may convey and the transceiver 101 may receive firstsensor data corresponding to the first measurement and second sensordata corresponding to the second measurement. In some embodiments, thestep 1108 may include the transceiver 101 receiving the first sensordata.

In some embodiments, the method 1100 may include a step 1110 in whichthe transceiver 101 (or other device) may calculate an interstitialfluid analyte level rate of change R_(ISF) based on at least the firstsensor data, the second sensor data, and a diffusion rate of the firstdiffusion barrier. In some embodiments, R_(ISF) may be calculatedfurther based on a diffusion rate of the second diffusion barrier 121.In embodiments with more than two diffusion barriers, these diffusionrates and additional sensor data may also be taken into account whencalculating R_(ISF) in step 1108.

In some embodiments where two transducers are used, R_(ISF) may becalculated according to the following formula, in which C_(G1)represents the analyte measurement from the first transducer 107, C_(G0)represents the analyte measurement from the second transducer 106, τ₁represents the delay associated with the first diffusion barrier 120,and τ₀ represents the delay associated with the second diffusion barrier121, if present.

$R_{ISF} \approx \frac{{C_{G_{1}}(t)} - {C_{G_{0}}(t)}}{\tau_{1} - \tau_{0}}$

In some embodiments, the method 1100 may include a step 1112 in whichthe transceiver 101 (or other device) may calculate a blood analytelevel based on the interstitial fluid analyte level (as measured by thefirst and/or second transducers) and R_(ISF) as calculated in step 1108.In some embodiments, blood analyte level C_(B) may be calculatedaccording to the following formula, in which p₁ represents the rate atwhich analyte in the interstitial fluid is consumed (e.g., by cells) andp₂ represents the rate at which glucose diffuses from the blood vesselto the interstitial fluid immediate proximate the sensor, and C_(G0)represents the analyte measurement from the second transducer (which maybe associated with a shorter lag time).

${C_{B}(t)} = {{\frac{1}{p_{2}}R_{ISF}} + {\left( {1 + \frac{p_{1}}{p_{2}}} \right){C_{G_{0}}(t)}}}$

In some embodiments, the method 1100 may include a step 1114 in whichthe transceiver 101 may be removed from the proximity of the sensor 100.The transceiver 101 may be removed from the proximity of the sensor 100at any time after the first sensor data and second sensor data arereceived. Further, the transceiver 101 may be removed before additionalmeasurements are performed. In this manner, the transceiver 101 may bepositioned (e.g., swiped) proximate to the sensor 100 for a brief timesufficient to perform a single measurement cycle and removed from theproximity of the sensor 100 immediately thereafter.

Embodiments of the present invention have been fully described abovewith reference to the drawing figures. Although the invention has beendescribed based upon these preferred embodiments, it would be apparentto those of skill in the art that certain modifications, variations, andalternative constructions could be made to the described embodimentswithin the spirit and scope of the invention. For example, although theinvention is described above in the context of an analyte monitoringsystem that calculates blood analyte levels indirectly usingmeasurements of analyte levels in interstitial fluid, the invention isapplicable to any monitoring system that calculates levels in a firstmedium using measurements of levels in a second medium.

The invention claimed is:
 1. A sensor configured for at least partialplacement in an analyte-containing medium, the sensor comprising: afirst transducer that exhibits one or more detectable properties basedon an amount or concentration of the analyte in proximity to the firsttransducer; a first diffusion barrier arranged such that, when thesensor is placed in the medium, the analyte contained in the mediumdiffuses through the first diffusion barrier before reaching the firsttransducer, wherein the first diffusion barrier is configured such thatthe analyte contained in the medium diffuses through the first diffusionbarrier at a first diffusion rate r₁; and a second transducer thatexhibits one or more detectable properties based on the amount orconcentration of the analyte in proximity to the second transducer,wherein no diffusion barrier is disposed over the second transducer suchthat, when the sensor is placed in the medium, the analyte contained inthe medium need not diffuse through a diffusion barrier before reachingthe second transducer; wherein, when the sensor is placed in the medium,the analyte contained in the medium reaches the second transducer beforethe analyte contained in the medium reaches the first transducer.
 2. Thesensor of claim 1, wherein the first diffusion barrier is disposed overthe first transducer, and the first diffusion barrier is configured suchthat, when the sensor is placed in the medium, the first diffusionbarrier at least partially inhibits diffusion of the analyte to thefirst transducer.
 3. The sensor of claim 1, further comprising a thirdtransducer that exhibits one or more detectable properties based on theamount or concentration of the analyte in proximity to the thirdtransducer.
 4. The sensor of claim 3, further comprising a seconddiffusion barrier arranged such that, when the sensor is placed in themedium, the analyte contained in the medium diffuses through the seconddiffusion barrier before reaching the third transducer, wherein thesecond diffusion barrier is configured such that the analyte containedin the medium diffuses through the second diffusion barrier at a seconddiffusion rate r₂, wherein r₁ is greater than r₂.
 5. The sensor of claim1, wherein the first transducer comprises a first polymer graft andfirst indicator molecules, and the second transducer comprises a secondpolymer graft and second indicator molecules.
 6. An analyte monitoringsystem, the system comprising: a sensor configured for at least partialplacement in an interstitial fluid, the sensor comprising: a firsttransducer that exhibits one or more detectable properties based on anamount or concentration of an analyte in proximity to the firsttransducer; a first diffusion barrier arranged such that, when thesensor is placed in the interstitial fluid, the analyte contained in theinterstitial fluid diffuses through the first diffusion barrier beforereaching the first transducer, wherein the first diffusion barrier isconfigured such that the analyte contained in the interstitial fluiddiffuses through the first diffusion barrier at a first diffusion rater₁; and a second transducer that exhibits one or more detectableproperties based on the amount or concentration of the analyte inproximity to the second transducer, wherein no diffusion barrier isdisposed over the second transducer such that, when the sensor is placedin the interstitial fluid, the analyte contained in the interstitialfluid need not diffuse through a diffusion barrier before reaching thesecond transducer; and a transceiver configured to: receive first sensordata collected from the first transducer; receive second sensor datacollected from the second transducer; calculate an interstitial fluidanalyte level rate of change based on at least the first sensor data,the second sensor data, and the first diffusion rate r₁.
 7. The analytemonitoring system of claim 6, wherein the first transducer comprises afirst polymer graft and first indicator molecules, and the secondtransducer comprises a second polymer graft and second indicatormolecules.
 8. A method for detecting the rate of change of an analyteconcentration in a medium, the method comprising: using a firsttransducer of a sensor of an analyte monitoring system to exhibit one ormore detectable properties based on an amount or concentration of ananalyte in proximity to the first transducer, wherein a first diffusionbarrier of the sensor is arranged such that, when the sensor is placedin the interstitial fluid, the analyte contained in the interstitialfluid diffuses through the first diffusion barrier before reaching thefirst transducer, and the first diffusion barrier is configured suchthat the analyte contained in the interstitial fluid diffuses throughthe first diffusion barrier at a first diffusion rate r₁; using a secondtransducer of the sensor to exhibit one or more detectable propertiesbased on the amount or concentration of the analyte in proximity to thesecond transducer, wherein no diffusion barrier is disposed over thesecond transducer such that, when the sensor is placed in theinterstitial fluid, the analyte contained in the interstitial fluid neednot diffuse through a diffusion barrier before reaching the secondtransducer; using the sensor to perform a first measurement of the oneor more detectable properties exhibited by the first transducer and asecond measurement of the one or more detectable properties exhibited bythe second transducer; using a transceiver of the analyte monitoringsystem to receive from the sensor at least first sensor datacorresponding to the first measurement and second sensor datacorresponding to the second measurement; using a processor of thetransceiver to calculate an analyte level rate of change based on atleast the first sensor data, the second sensor data, and a firstdiffusion rate r₁ of the analyte through the first diffusion barrier. 9.The method of claim 8, further comprising using the processor of thetransceiver to calculate an interstitial fluid analyte level based on atleast one of the first sensor data and the second sensor data; and usingthe processor of the transceiver to calculate a blood analyte levelbased on the interstitial fluid analyte level and the analyte level rateof change.
 10. The method of claim 8, further comprising: using thetransceiver to detect that the transceiver is positioned within aproximity of the sensor; using the transceiver to, in response todetecting that the transceiver is proximate the sensor, transmittingfrom the transceiver to the sensor power sufficient to perform the firstmeasurement and the second measurement, the transmitted power being usedto perform the first measurement and the second measurement; afterreceiving from the sensor the first sensor data and the second sensordata, and before additional measurements are performed, removing thetransceiver from the proximity of the sensor.
 11. The method of claim 8,wherein the first transducer comprises a first polymer graft and firstindicator molecules, and the second transducer comprises a secondpolymer graft and second indicator molecules.